Transforming growth factor-α attenuates hepatic fibrosis: possible involvement of matrix metalloproteinase-1
Transforming growth factor-α attenuates hepatic fibrosis: possible involvement of matrix metalloproteinase-1
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DOI：
10.1111/j.1478-3231.2011.02475.x
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发表时间：
2011-04-01
影响因子：
6.7
通讯作者：
Mori, Masatomo
中科院分区：
文献类型：
--
作者：
Ohyama, Tatsuya;Yamazaki, Yuichi;Mori, Masatomo
背景：转化生长因子（TGF）-α 对纤维化的影响因细胞类型而异，并且 TGF-α 在肝纤维化中的作用尚未完全阐明。方法：我们使用缺乏蛋氨酸和胆碱（MCD）饮食的表达 TGF-α 的转基因小鼠以及人肝星状细胞（HSC）系 LX-2、大鼠和人原代 HSC，研究了 TGF-α 对肝纤维化的影响。结果：虽然金属蛋白酶组织抑制剂-1和α1(I)胶原蛋白mRNA的表达水平没有变化，但与野生型小鼠相比，用MCD饮食喂养TGF-α转基因小鼠会导致基质金属蛋白酶-1的小鼠功能类似物(MMP-1)、MMP-13 mRNA和蛋白质的表达更高，并减轻肝纤维化。 TGF-α过度表达并不影响MCD饮食喂养小鼠的脂肪变性、氧化应激和肝脏炎症的程度。体外，TGF-α 对纤维形成和抗纤维形成基因表达的影响因细胞类型而异。 TGF-α 增加了 LX-2 细胞中 MMP-1 mRNA 的表达，而吉非替尼完全阻断了这一表达。细胞外信号调节激酶 (ERK) 1/2、c-Jun N 末端激酶和 p38 通路参与 LX-2 细胞中 MMP-1 mRNA 的表达。虽然TGF-α增加了p38的磷酸化，但p38抑制剂激活了RAS-ERK通路并增加了TGF-α诱导的MMP-1 mRNA表达，这表明LX-2细胞中RAS-ERK和p38通路之间可能存在串扰。结论：TGF-α 可能减轻肝纤维化，部分原因是上调 MMP-1 的表达。纤维化和抗纤维化基因表达之间以及 RAS-ERK 和 p38 通路活性之间的平衡可能对于纤维化过程至关重要。
Background: The effect of transforming growth factor (TGF)-alpha on fibrosis varies between cell types and the role of TGF-alpha in hepatic fibrosis has not been fully elucidated. Methods: We examined the effect of TGF-alpha on hepatic fibrosis using TGF-alpha-expressing transgenic mice fed a methionine- and choline-deficient (MCD) diet and human hepatic stellate cells (HSCs) line LX-2, rat and human primary HSCs. Results: Although the expression levels of the tissue inhibitor of metalloproteinases-1 and alpha 1(I) collagen mRNA were unchanged, feeding the TGF-alpha transgenic mice the MCD diet resulted in greater expression of the murine functional analogue of matrix metalloproteinase-1 (MMP-1), MMP-13 mRNA and protein and attenuated hepatic fibrosis compared with wild-type mice. TGF-alpha overexpression did not affect the extent of the steatosis, oxidative stress and hepatic inflammation in the MCD diet-fed mice. The effect of TGF-alpha on the fibrogenic and anti-fibrogenic gene expressions varied between cell types in vitro. TGF-alpha increased MMP-1 mRNA expressions that were completely blocked by gefitinib in LX-2 cells. The extracellular signal-regulated kinase (ERK) 1/2, c-Jun N-terminal kinase and p38 pathways were involved in MMP-1 mRNA expression in LX-2 cells. Although TGF-alpha increased the phosphorylation of p38, the p38 inhibitor activated the RAS- ERK pathway and increased TGF-alpha-induced MMP-1 mRNA expression, which suggested that there may be a crosstalk between the RAS- ERK and the p38 pathways in LX-2 cells. Conclusions: The TGF-alpha may attenuate hepatic fibrosis in part because of upregulation of the expression of MMP-1. The balance between fibrogenic and anti-fibrogenic gene expression and between the activity of the RAS- ERK and the p38 pathways may be crucial for the fibrotic process.